Despite marijuana being the most commonly abused illicit drug in the U.S., the mechanisms of action for known risk factors that increase susceptibility to marijuana's rewarding effects remain unknown. Building upon our studies on the neural mechanisms of cue-elicited craving in marijuana dependence, the goal of these studies is to characterize the mechanisms by which genetic and environmental factors moderate the brain's response to marijuana cues. Specifically, we will test the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes, which are associated with craving for marijuana, and, an environmental factor with links to the development of substance abuse, and which our early findings suggest is positively associated with response to cues, namely early life stress. To that end, we will record fMRI BOLD response in current heavy marijuana users during a marijuana cue exposure task, and determine the main effects and interactions between the genetic (i.e., CNR1, FAAH) and environmental (i.e., early life stress) variables. Based on our preliminary findings, we predict that the genetic and environmental variables will moderate the neural response to cues in reward areas of the brain. The proposed work will corroborate the contributions of genetic (i.e., CNR1 and FAAH genes) and environmental (i.e., early life stress) risk factors towards marijuana dependence and, more importantly, uncover the mechanisms by which these known risk factors increase morbidity for marijuana dependence. The successful completion of these studies will help identify individuals who are at risk for marijuana dependence and inform on more targeted treatment. PUBLIC HEALTH RELEVANCE: The reasons why the mechanisms by which risk factors increase risk for marijuana dependence must be uncovered are: (1) Marijuana continues to be the most widely used illicit drug, (2) There has been a large increase in rate of treatment admission for marijuana dependence in the last decade, (3) Rate of initiation is highest during the critical neurodevelopmental period of adolescence, and (4) There continues to be a large gap in the literature on biobehavioral mechanisms that lead to marijuana dependence. The proposed studies are designed to test how specific genetic variations and environmental factors that are associated with marijuana dependence influence the brain's sensitivity to marijuana cues. Improvements in our understanding of these neurobiological mechanisms will lead to better preventative intervention strategies that identify high-risk individuals and target specific neurobiological systems.